3-Substituted-ureido-N-pyridyl benzamides

ABSTRACT

Benzamide derivatives of the formula: ##STR1## wherein R 1  is a hydrogen atom, a methyl group or a methoxy group; R 2  is a straight-chain or branched-chain alkyl group having 2 to 8 carbon atoms, a substituted phenyl group, or group --NHR 4 , R 4  being a hydrogen atom, a straight-chain or branched-chain or cyclic alkyl group having 1 to 6 carbon atoms, or a phenyl group that may have a substituent on the nucleus; R 3  is a hydrogen atom or one or two alkyl groups having 1 to 4 carbon atoms and n is 0 or 1, a process for preparing these derivatives, and pharmaceutical compositions containing the same are provided. 
     The compounds of the above formula have the action to reduce the blood glucose level and, therefore, are useful as medicines.

The present invention relates to benzamide derivatives of the formula: ##STR2## (wherein R₁ is a hydrogen atom, a methyl group or a methoxy group; R₂ is a straight-chain or branched-chain alkyl group having 2 to 8 carbon atoms, a substituted phenyl group, or group --NHR₄, R₄ being a hydrogen atom, a straight-chain or branched-chain or cyclic alkyl group having 1 to 6 carbon atoms, or a phenyl group that may have a substituent on the nucleus; R₃ is a hydrogen atom or one or two alkyl groups having 1 to 4 carbon atoms, and n is 0 or 1), a process for preparing these derivatives, and pharmaceutical compositions containing them. Examples of the substituent of the phenyl group of R₂ and R₄ in the formula (I) are a halogen atom, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms.

The compounds of the present invention that are represented by formula (I) are useful as medicines since they have the ability to reduce the blood glucose level.

One method of producing the compounds of the present invention comprises the steps of reacting 3-nitrobenzoyl chloride with amines in the presence of a base to form 3-nitrobenzamide derivatives and reducing them by a conventional technique to form 3-aminobenzamide derivatives, and reacting them with a carboxylic acid chloride or an isocyanate. This method is illustrated by the following reaction scheme wherein X is a halogen atom and the other symbols have the same meanings as defined above: ##STR3##

Compound (II) is reacted with aminopyridines under the conditions conventionally used for the reaction of forming acid amides; for example, the two compounds are reacted in a solvent such as acetone, tetrahydrofuran or dioxane, preferably in the presence of a base such as triethylamine or pyridine, at a temperature between 0° and 30° C. for a period of 1 to 5 hours.

Compound (III) can be readily converted to compound (IV) by catalytic reduction using a catalyst such as palladium-carbon, Raney's nickel or platinum dioxide.

Compound (IV) can be converted to the end compound (I) by reacting it with a reactive derivative of carboxylic acid or an isocyanate in the presence of a solvent such as tetrahydrofuran, dioxane, benzene or toluene, in the presence of a base such as triethylamine, pyridine dimethylanilin or picoline, at a temperature between 0° and 100° C. for a period of 1 to 48 hours.

The compound (I) so obtained is highly capable of reducing the blood glucose level and can be used as a medicine to treat diabetes.

The pharmaceutical composition containing the compound (I) of the present invention can be administered to human beings orally or parenterally by intramuscular, subcutaneous or intravenous injection or in the form of a suppository. The composition can be formulated in a suitable dosal form by any of the conventional drug-making techniques, and among the suitable drug forms are tablets, slow-release agents, powders, capsules, suspensions, injections and suppositories.

The present invention is now described in greater detail by reference to the following examples and experiments to which the scope of the invention is by no means limited.

EXAMPLE 1

To a mixture of 2-aminopyridine (28.2 g), triethylamine (45 ml) and acetone (600 ml), 3-nitrobenzoyl chloride (55.8 g) was gradually added with stirring under ice cooling. The mixture was stirred for 30 minutes under the same condition, then for one hour at room temperature. Thereafter, the reaction solution was poured into 3 liters of water, and the resulting crystal was collected by filtration, washed with water, and recrystallized from methanol to provide 58.5 g of 3-nitro-N-2-pyridylbenzamide as a colorless acicular crystal (yield: 80%, m.p. 156°-157° C.). Hydrogen was bubbled into a mixture of the 3-nitro-N-2-pyridylbenzamide (15.9 g), 10% palladium-carbon (1.5 g) and ethanol (300 ml). After a stoichiometric amount of hydrogen was absorbed, the catalyst was removed, the reaction mixture was concentrated under vacuum, and the residue was recrystallized from ethanol to provide 7.2 g of a colorless acicular crystal of 3-amino-N-2-pyridylbenzamide (yield: 52%, m.p. 113°-115° C.). To a mixture of the 3-amino-N-2-pyridylbenzamide (6.4 g), triethylamine (4.5 ml) and acetone (60 ml), propionic acid chloride (2.8 g) was gradually added with stirring at room temperature. After one hour of stirring, the reaction mixture was poured into 200 ml of water which was then made weakly alkaline by gradually adding a 10% solution of sodium hydroxide. The resulting crystal was collected by filtration, washed with water and recrystallized from methanol to provide 7.0 g of 3-propionyl-N-2-pyridylbenzamide as a colorless acicular crystal (compound 1) (yield: 87%, m.p. 128°-129° C.).

Elemental analysis: Calculated for C₁₅ H₁₅ N₃ O₂ (%): C, 66.90; H, 5.61; N, 15.61; Found (%): C, 66.97; H, 5.65; N, 15.52.

EXAMPLES 2-36

Compounds 2 to 36 having the characteristics shown in Table 1 below were prepared as in Example 1.

                                      TABLE 1                                      __________________________________________________________________________      ##STR4##                                                                       No.                                                                                R.sub.1                                                                            R.sub.2    n                                                                                 ##STR5##  formulamolecular                                                                      m.p. (°C.)                                                                    (%)yield                                                                                CHNelemental                                                                  analysis                 __________________________________________________________________________     2   H   C.sub.2 H.sub.5                                                                           0                                                                                  ##STR6## C.sub.15 H.sub.15 N.sub.3 O.sub.2                                                     197-199                                                                              83 cal'd (%) found                                                                      66.90 66.94                                                                       5.61 5.56                                                                         15.61 15.58          3 "   "          1                                                                                  ##STR7## C.sub.16 H.sub.17 N.sub.3 O.sub.2                                                     108-109                                                                              74 cal'd (%) found                                                                      67.82 67.85                                                                       6.05 6.02                                                                         14.83 14.87          4 "   "          1                                                                                  ##STR8## "      140-141                                                                              78 cal'd (%) found                                                                      67.82 67.76                                                                       6.05 6.57                                                                         14.83 14.88          5 "   "          0                                                                                  ##STR9## "      60-61 71 cal'd (%) found                                                                      67.82 67.78                                                                       6.05 6.59                                                                         14.83 14.84          6 "   "          0                                                                                  ##STR10##                                                                               C.sub.17 H.sub.19 N.sub.3 O.sub.2                                                     81-82 85 cal'd (%) found                                                                      68.66 68.62                                                                       6.44 6.45                                                                         14.13 14.19          7 "   n-C.sub.3 H.sub.7                                                                         1                                                                                  ##STR11##                                                                               "      155-156                                                                              81 cal' d (%) found                                                                     68.66 68.63                                                                       6.44 6.49                                                                         14.13 14.10          8 "   "          0                                                                                  ##STR12##                                                                               "      84-85 82 cal'd (%) found                                                                      68.66 68.67                                                                       6.44 6.47                                                                         14.13 14.08          9 "   i-C.sub.3 H.sub.7                                                                         0  "         "      201-202                                                                              88 cal'd (%)                                                                            68.66                                                                             6.44                                                                              14.13                                                              found (%)                                                                            68.69                                                                             6.43                                                                              14.17                10                                                                               "   n-C.sub.4 H.sub.9                                                                         1                                                                                  ##STR13##                                                                               C.sub.18 H.sub.21 N.sub.3 O.sub.2                                                     97-98 68 cal'd (%) found                                                                      69.43 69.38                                                                       6.80 6.77                                                                         13.50 13.55          11                                                                               "   "          0                                                                                  ##STR14##                                                                               "      133-134                                                                              75 cal'd (%) found                                                                      69.43 69.45                                                                       6.80 6.79                                                                         13.50 13.54          12                                                                               "   i-C.sub.4 H.sub. 9                                                                        0  "         "      90-91 79 cal'd (%)                                                                            69.43                                                                             6.80                                                                              13.50                                                              found (%)                                                                            69.41                                                                             6.83                                                                              13.52              13  "   n-C.sub.5 H.sub.11                                                                        0  "         C.sub.19 H.sub.23 N.sub.3 O.sub.2                                                     87-88 86 cal'd (%)                                                                            70.13                                                                             7.12                                                                              12.91                                                              found (%)                                                                            70.19                                                                             7.06                                                                              12.85              14  "   n-C.sub.6 H.sub.13                                                                        0  "         C.sub.20 H.sub.25 N.sub.3 O.sub.2                                                     94-95 82 cal'd (%)                                                                            70.77                                                                             7.43                                                                              12.38                                                              found (%)                                                                            70.72                                                                             7.48                                                                              12.44              15  "   n-C.sub.7 H.sub.15                                                                        0  "         C.sub.21 H.sub.27 N.sub.3 O.sub.2                                                     97-98 75 cal'd (%)                                                                            71.36                                                                             7.70                                                                              11.89                                                              found (%)                                                                            71.31                                                                             7.65                                                                              11.95                16                                                                               "   n-C.sub.8 H.sub.17                                                                        0                                                                                  ##STR15##                                                                               C.sub.22 H.sub.29 N.sub.3 O.sub.2                                                     100-101                                                                              81 cal'd (%) found                                                                      71.90 71.96                                                                       7.95 7.99                                                                         11.44  11.48         17                                                                               "                                                                                   ##STR16## 0                                                                                  ##STR17##                                                                               C.sub.20 H.sub.17 N.sub.3 O.sub.2                                                     229-231                                                                              91 cal'd (%) found                                                                      72.49 72.53                                                                       5.17 5.14                                                                         12.68 12.67          18                                                                               "   "          1  "         C.sub.21 H.sub.19 N.sub.3 O.sub.2                                                     225-227                                                                              84 cal'd (%)                                                                            73.02                                                                             5.55                                                                              12.17                                                              found (%)                                                                            73.10                                                                             5.51                                                                              12.22                19                                                                               "   "          0                                                                                  ##STR18##                                                                               "      176-177                                                                              86 cal'd (%) found                                                                      73.02 73.03                                                                       5.55 5.53                                                                         12.17 12.14          20                                                                               "                                                                                   ##STR19## 0  "         C.sub.21 H.sub.19 N.sub.3 O.sub.3                                                     183-185                                                                              80 cal'd (%) found                                                                      69.79 69.84                                                                       5.30 5.33                                                                         11.63 11.67          21                                                                               CH.sub.3                                                                           C.sub.2 H.sub.5                                                                           1                                                                                  ##STR20##                                                                               C.sub.17 H.sub.19 N.sub.3 O.sub.2                                                     188-200                                                                              87 cal'd (%) found                                                                      68.66 68.64                                                                       6.44 6.41                                                                         14.13 14.18          22                                                                               "   "          0                                                                                  ##STR21##                                                                               "      157-158                                                                              88 cal'd (%) found                                                                      68.66 68.62                                                                       6.44 6.45                                                                         14.13 14.16          23                                                                               "   n-C.sub.3 H.sub.7                                                                         1                                                                                  ##STR22##                                                                               C.sub.18 H.sub.21 N.sub.3 O.sub.2                                                     179-180                                                                              76 cal'd (%) found                                                                      69.43 69.49                                                                       6.80 6.88                                                                         13.50 13.45          24                                                                               "   "          0                                                                                  ##STR23##                                                                               "      151-152                                                                              78 cal'd (%) found                                                                      69.43 69.48                                                                       6.80 6.82                                                                         13.50 13.52          25                                                                               "   i-C.sub.3 H.sub.7                                                                         1                                                                                  ##STR24##                                                                               "      140-141                                                                              73 cal'd (%) found                                                                      69.43 69.40                                                                       6.80 6.85                                                                         13.50 13.54          26                                                                               "   "          0                                                                                  ##STR25##                                                                               "      200-201                                                                              89 cal'd (%) found                                                                      69.43 69.47                                                                       6.80 6.86                                                                         13.50 13.55          27                                                                               "   n-C.sub.4 H.sub.9                                                                         1                                                                                  ##STR26##                                                                               C.sub.19 H.sub.23 N.sub.3 O.sub.2                                                     177-178                                                                              72 cal'd (%) found                                                                      70.13 70.09                                                                       7.12 7.18                                                                         12.91 12.93          28                                                                               "   "          0                                                                                  ##STR27##                                                                               "      152-153                                                                              71 cal'd (%) found                                                                      70.13 70.14                                                                       7.12 7.15                                                                         12.91 12.98          29                                                                               OCH.sub.3                                                                          C.sub.2 H.sub.5                                                                           1                                                                                  ##STR28##                                                                               C.sub.17 H.sub.19 N.sub.3 O.sub.3                                                     86-87 74 cal'd (%) found                                                                      65.16 65.19                                                                        6.11 6.14                                                                        13.41 13.37          30                                                                               "   "          0                                                                                  ##STR29##                                                                               "      142-143                                                                              78 cal'd (%) found                                                                      65.16 65.18                                                                       6.11 6.08                                                                         13.41 13.44          31                                                                               "   n-C.sub.3 H.sub.7                                                                         1                                                                                  ##STR30##                                                                               C.sub.18 H.sub.21 N.sub.3 O.sub.3                                                     139-140                                                                              76 cal'd (%) found                                                                      66.03 66.06                                                                       6.47 6.42                                                                         12.84 12.81          32                                                                               "   "          0                                                                                  ##STR31##                                                                               "      77-78 84 cal'd (%) found                                                                      66.03 66.01                                                                       6.47 6.41                                                                         12.84 12.89          33                                                                               "   i-C.sub.3 H.sub.7                                                                         1                                                                                  ##STR32##                                                                               "      174-175                                                                              75 cal'd (%) found                                                                      66.03 66.07                                                                       6.47 6.51                                                                         12.84 12.87          34                                                                               "   "          0                                                                                  ##STR33##                                                                               "      150-151                                                                              82 cal'd (%) found                                                                      66.03 66.09                                                                       6.47 6.43                                                                         12.84 12.80          35                                                                               "   n-C.sub.4 H.sub.9                                                                         1                                                                                  ##STR34##                                                                               C.sub.19 H.sub.23 N.sub.3 O.sub.3                                                     130-131                                                                              73 cal'd (%) found                                                                      66.84 66.89                                                                       6.79 6.82                                                                         12.31 12.34          36                                                                               "   "          0                                                                                  ##STR35##                                                                               "      102-103                                                                              79 cal'd (%) found                                                                      66.84 66.87                                                                       6.79 6.84                                                                         12.31              __________________________________________________________________________                                                                 12.28         

EXAMPLE 37

A mixture of the 3-amino-N-2-pyridylbenzamide (6.4 g), acetone (60 ml), methyl isocyanate (1.8 ml) and a catalytic amount of triethylamine were stirred at room temperature for 24 hours. The resulting crystal was collected by filtration and recrystallized from acetone to provide 6.9 g of 3-(3-methylureido)-N-2-pyridylbenzamide as a colorless acicular crystal (compound 37) (yield: 85%, m.p. 163°-164° C.).

Elemental analysis: Calculated for C₁₄ H₁₄ N₄ O₂ (%): C, 62.21; H, 5.22; N, 20.73; Found (%): C, 62.18; H, 5.27; N, 20.78.

EXAMPLES 38-75

Compounds 38 to 75 having the characteristics shown in Table 2 below were prepared as in Example 37.

                                      TABLE 2                                      __________________________________________________________________________      ##STR36##                                                                      No.                                                                               R.sub.1                                                                            R.sub.2     n                                                                                ##STR37##                                                                                formulamolecular                                                                       m.p. (°C.)                                                                    (%)yield                                                                                CHNelemental                                                                  analysis                 __________________________________________________________________________     38 H   NHC.sub.2 H.sub.5                                                                          0                                                                                 ##STR38##                                                                               C.sub.15 H.sub.16 N.sub.4 O.sub.2                                                      154-155                                                                              81 cal'd (%) found                                                                      63.36 63.39                                                                       5.67 5.62                                                                         19.71 19.78          39                                                                              "   NHn-C.sub.3 H.sub.7                                                                        0 "         C.sub.16 H.sub. 18 N.sub.4 O.sub.2                                                     158-159                                                                              83 cal'd (%)                                                                            64.41                                                                             6.08                                                                              18.78                                                              found (%)                                                                            64.44                                                                             6.13                                                                              18.82              40 "   NHi-C.sub.3 H.sub.7                                                                        0 "         "       173-174                                                                              88 cal'd (%)                                                                            64.41                                                                             6.08                                                                              18.78                                                              found (%)                                                                            64.45                                                                             6.06                                                                              18.73                41                                                                              "                                                                                   ##STR39##  0 "         C.sub.19 H.sub.22 N.sub.4 O.sub.2                                                      191-193                                                                              91 cal'd (%) found                                                                      67.43 67.39                                                                       6.55 6.57                                                                         16.56 16.52          42                                                                              "   NHC.sub.2 H.sub.5                                                                          0                                                                                 ##STR40##                                                                               C.sub.15 H.sub.16 N.sub.4 O.sub.2                                                      209-210                                                                              85 cal'd (%) found                                                                      63.36 63.30                                                                       5.67 5.62                                                                         19.71 19.75          43                                                                              "   NHi-C.sub.3 H.sub.7                                                                        1                                                                                 ##STR41##                                                                               C.sub.17 H.sub.20 N.sub.4 O.sub.2                                                      165-166                                                                              82 cal'd (%) found                                                                      65.36 65.33                                                                        6.45 6.41                                                                        17.94 17.98          44                                                                              "   NHCH.sub.3  0                                                                                 ##STR42##                                                                               C.sub.15 H.sub.16 N.sub.4 O.sub.2                                                      186-187                                                                              73 cal'd (%) found                                                                      63.36 63.32                                                                       5.67 5.61                                                                         19.71 19.76          45                                                                              "   NHC.sub.2 H.sub.5                                                                          0 "         C.sub.16 H.sub.18 N.sub.4 O.sub.2                                                      185-186                                                                              79 cal'd (%)                                                                            64.41                                                                             6.08                                                                              18.78                                                              found (%)                                                                            64.37                                                                             6.06                                                                              18.72              46 "   NHn-C.sub.3 H.sub.7                                                                        0 "         C.sub.17 H.sub.20 N.sub.4 O.sub.2                                                      149-150                                                                              81 cal'd (%)                                                                            65.36                                                                             6.45                                                                              17.94                                                              found (%)                                                                            65.34                                                                             6.49                                                                              17.99              47 "   NHi-C.sub.3 H.sub.7                                                                        0 "         "       183-184                                                                              80 cal'd (%)                                                                            65.36                                                                             6.45                                                                              17.94                                                              found (%)                                                                            65.31                                                                             6.42                                                                              17.98              48 "   NHn-C.sub.4 H.sub.9                                                                        0 "         C.sub.18 H.sub.22 N.sub.4 O.sub.2                                                      157-158                                                                              74 cal'd (%)                                                                            66.23                                                                             6.79                                                                              17.17                                                              found (%)                                                                            66.28                                                                             6.85                                                                              17.21                49                                                                              "                                                                                   ##STR43##  0 "         C.sub.20 H.sub.24 N.sub.4 O.sub.2                                                      193-194                                                                              88 cal'd (%) found                                                                      68.16 68.12                                                                       6.86 6.83                                                                         15.90 15.94          50                                                                              "                                                                                   ##STR44##  0 "         C.sub.20 H.sub.18 N.sub.4 O.sub.2                                                      182-183                                                                              89 cal'd (%) found                                                                      69.35 69.37                                                                       5.24 5.22                                                                         16.18 16.14          51                                                                              "                                                                                   ##STR45##  0 "         C.sub.20 H.sub.17 ClN.sub.4 O.sub.2                                                    216-217                                                                              83 cal'd (%) found                                                                      63.07 63.04                                                                       4.50 4.58                                                                         14.71 14.76          52                                                                              "   NHCH.sub.3  0                                                                                 ##STR46##                                                                               C.sub.16 H.sub.18 N.sub.4 O.sub.2                                                      139-140                                                                              76 cal'd (%)  found                                                                     64.41 64.36                                                                       6.08 6.05                                                                         18.78 18.74          53                                                                              "   NHC.sub.2 H.sub.5                                                                          0 "         C.sub.17 H.sub.20 N.sub.4 O.sub.2                                                      202-204                                                                              84 cal'd (%)                                                                            65.36                                                                             6.45                                                                              17.94                                                              found (%)                                                                            65.39                                                                             6.44                                                                              17.88              54 "   NHn-C.sub.3 H.sub.7                                                                        0 "         C.sub.18 H.sub.22 N.sub.4 O.sub.2                                                      192-193                                                                              82 cal'd (%)                                                                            66.23                                                                             6.79                                                                              17.17                                                              found (%)                                                                            66.27                                                                             6.72                                                                              17.24              55 "   NHi-C.sub.3 H.sub.7                                                                        0 "         "       172-173                                                                              88 cal'd (%)                                                                            66.23                                                                             6.79                                                                              17.17                                                              found (%)                                                                            66.26                                                                             6.76                                                                              17.21                56                                                                              "                                                                                   ##STR47##  0 "         C.sub.21 H.sub.26 N.sub.4 O.sub.2                                                      148-150                                                                              89 cal'd (%) found                                                                      68.83 68.87                                                                       7.15 7.17                                                                         15.29 15.24          57                                                                              CH.sub.3                                                                           NHCH.sub.3  0                                                                                 ##STR48##                                                                               C.sub.15 H.sub.16 N.sub.4 O.sub.2                                                      218-220                                                                              86 cal'd (%) found                                                                      63.36 63.31                                                                       5.67 5.62                                                                         19.71 19.76          58                                                                              "   NHC.sub.2 H.sub.5                                                                          0 "         C.sub.16 H.sub.18 N.sub.4 O.sub.2                                                      210-212                                                                              75 cal'd (%)                                                                            64.41                                                                             6.08                                                                              18.78                                                              found (%)                                                                            64.48                                                                             6.06                                                                              18.73              59 "   NHn-C.sub.3 H.sub.7                                                                        0 "         C.sub.17 H.sub.20 N.sub.4 O.sub.2                                                      220-221                                                                              77 cal'd (%)                                                                            65.36                                                                             6.45                                                                              17.94                                                              found (%)                                                                            65.33                                                                             6.42                                                                              17.99              60 "   NHi-C.sub.3 H.sub.7                                                                        0 "         "       238-240                                                                              71 cal'd (%)                                                                            65.36                                                                             6.45                                                                              17.94                                                              found (%)                                                                            65.30                                                                             6.41                                                                              17.98                61                                                                              "   NHCH.sub.3  0                                                                                 ##STR49##                                                                               C.sub.16 H.sub.18 N.sub.4 O.sub.2                                                      214-215                                                                              79 cal'd (%) found                                                                      64.41 64.48                                                                       6.08 6.03                                                                         18.78 18.75          62                                                                              "   NHC.sub.2 H.sub.5                                                                          0 "         C.sub.17 H.sub.20 N.sub.4 O.sub.2                                                      217-219                                                                              80 cal'd (%)                                                                            65.36                                                                             6.45                                                                              17.94                                                              found (%)                                                                            65.34                                                                             6.48                                                                              17.97              63 "   NHn-C.sub.3 H.sub.7                                                                        0 "         C.sub.18 H.sub.22 N.sub.4 O.sub.2                                                      178-179                                                                              86 cal'd (%)                                                                            66.23                                                                             6.79                                                                              17.17                                                              found (%)                                                                            66.27                                                                             6.75                                                                              17.12              64 "   NHi-C.sub.3 H.sub.7                                                                        0 "         "       180-181                                                                              82 cal'd (%)                                                                            66.23                                                                             6.79                                                                              17.17                                                              found (%)                                                                            66.28                                                                             6.79                                                                              17.18              65 "   NHn-C.sub.4 H.sub.9                                                                        0 "         C.sub.19 H.sub.24 N.sub.4 O.sub.2                                                      189-190                                                                              75 cal'd (%)                                                                            67.03                                                                             7.11                                                                              16.46                                                              found (%)                                                                            67.07                                                                             7.18                                                                              16.42                66                                                                              "                                                                                   ##STR50##  0 "         C.sub.21 H.sub.26 N.sub.4 O.sub.2                                                      192-193                                                                              92 cal'd (%) found                                                                      68.83 68.88                                                                       7.15 7.13                                                                          15.29 15.24         67                                                                              "                                                                                   ##STR51##  0 "         C.sub.21 H.sub.19 ClN.sub.4 O.sub.2                                                    235-237                                                                              88 cal'd (%) found                                                                      63.87 63.84                                                                       4.85 4.89                                                                         14.19 14.25          68                                                                              OCH.sub.3                                                                          NHCH.sub.3  0 "         C.sub.16 H.sub.18 N.sub.4 O.sub.3                                                      203-204                                                                              75 cal'd (%)                                                                            61.13                                                                             5.77                                                                              17.83                                                              found (%)                                                                            61.17                                                                             5.74                                                                              17.87              69 "   NHC.sub.2 H.sub.5                                                                          0 "         C.sub.17 H.sub.20 N.sub.4 O.sub.3                                                      165-166                                                                              72 cal'd (%)                                                                            62.18                                                                             6.14                                                                              17.06                                                              found (%)                                                                            62.24                                                                             6.19                                                                              17.02              70 "   NHn-C.sub.3 H.sub.7                                                                        0 "         C.sub.18 H.sub.22 N.sub.4 O.sub.3                                                      164-165                                                                              80 cal'd (%)                                                                            63.14                                                                             6.48                                                                              16.36                                                              found (%)                                                                            63.18                                                                             6.42                                                                              16.30              71 "   NHi-C.sub.3 H.sub.7                                                                        0 "         "       144-145                                                                              88 cal'd (%)                                                                            63.14                                                                             6.48                                                                              16.36                                                              found (%)                                                                            63.17                                                                             6.44                                                                              16.38              72 "   NHn-C.sub.4 H.sub.9                                                                        0 "         C.sub.19 H.sub.24 N.sub.4 O.sub.3                                                      147-148                                                                              76 cal'd (%)                                                                            64.02                                                                             6.79                                                                              15.72                                                              found (%)                                                                            64.09                                                                             6.72                                                                              15.76                73                                                                              "                                                                                   ##STR52##  0 "         C.sub.21 H.sub.26 N.sub.4 O.sub.3                                                      183-184                                                                              85 cal'd (%) found                                                                      65.95 65.91                                                                       6.85 6.89                                                                         14.65 14.63          74                                                                              "                                                                                   ##STR53##  0 "         C.sub.21 H.sub.19 ClN.sub.4 O.sub.3                                                    191-192                                                                              82 cal'd (%) found                                                                      61.39 61.32                                                                       4.66 4.60                                                                         13.64 13.59          75                                                                              H   NH.sub.2    0 "         C.sub.14 H.sub.14 N.sub.4 O.sub.2                                                      205-207                                                                              75 cal'd (%)                                                                            62.21                                                                             5.22                                                                              20.73                                                              found (%)                                                                            62.19                                                                             5.25                                                                              20.70              __________________________________________________________________________

EXPERIMENTS

Groups each consisting of five male DDY mice (5 weeks old and weighing 25-30 g) were fasted 16 hours and given an intravenous injection of 75 mg/kg of alloxan. Forty-eight hours later, aqueous solutions or suspensions containing 200 mg/kg of the compounds indicated in Table 3 were orally administered to the mice, and 150 minutes later, blood was drawn from their hearts and the glucose level was measured by the glucose oxidase method. The results are shown in Table 3 and Table 4, wherein the compound numbers are keyed to those used in Examples 1 to 75.

                  TABLE 3                                                          ______________________________________                                                   blood                  blood                                                   glucose level          glucose level                                 Compound  (mg/dl)    Compound    (mg/dl)                                       No.       mean ± S.D.                                                                            No.         mean ± S.D.                                ______________________________________                                         none      485 ± 28                                                                               19          396 ± 29**                                 (control)            20          390 ± 25***                                 1        389 ± 35**                                                                             21          421 ± 38*                                   2        371 ± 29***                                                                            22          424 ± 34*                                   3        392 ± 36**                                                                             23          419 ± 27**                                  4        403 ± 31**                                                                             24          405 ± 31**                                  5        368 ± 40***                                                                            25          390 ± 29***                                 6        379 ± 33***                                                                            26          378 ± 36***                                 7        411 ± 29**                                                                             27          384 ± 28***                                 8        415 ± 34**                                                                             28          391 ± 33**                                  9        420 ± 25**                                                                             29          412 ± 38*                                  10        399 ± 19***                                                                            30          418 ± 25*                                  11        385 ± 38**                                                                             31          390 ± 31***                                12        392 ± 25***                                                                            32          385 ± 40**                                 13        393 ± 25***                                                                            33          369 ± 29***                                14        385 ± 31***                                                                            34          396 ±  28**                                15        411 ± 28**                                                                             35          418 ± 33**                                 16        379 ± 33***                                                                            36          405 ± 29**                                 17        407 ± 40**                                                        18        405 ± 31**                                                        ______________________________________                                          *P < 0.05                                                                      **P < 0.01                                                                     ***P < 0.001                                                             

                  TABLE 4                                                          ______________________________________                                                   blood                  blood                                                   glucose level          glucose level                                 Compound  (mg/dl)    Compound    (mg/dl)                                       No.       mean ± S.D.                                                                            No.         mean ± S.D.                                ______________________________________                                         none      468 ± 31                                                                               56          388 ± 31**                                 (control)            57          325 ± 29***                                37        394 ± 28**                                                                             58          415 ± 26*                                  38        331 ± 41***                                                                            59          388 ± 32**                                 39        368 ± 32**                                                                             60          337 ± 24***                                40        392 ± 33**                                                                             61          369 ± 35**                                 41        401 ± 27**                                                                             62          386 ± 42**                                 42        383 ± 31**                                                                             63          363 ± 50**                                 43        349 ± 25***                                                                            64          392 ± 37**                                 44        377 ± 35**                                                                             65          354 ± 36***                                45        365 ± 28***                                                                            66          381 ± 29**                                 46        351 ± 35***                                                                            67          399 ± 27**                                 47        311 ± 30***                                                                            68          331 ± 29***                                48        390 ± 29**                                                                             69          362 ± 31***                                49        403 ± 34*                                                                              70          375 ± 34**                                 50        411 ± 27*                                                                              71          344 ± 36***                                51        385 ± 40**                                                                             72          366 ± 39**                                 52        378 ± 21***                                                                            73          321 ± 36***                                53        395 ± 33**                                                                             74          347 ± 38***                                54        342 ± 29***                                                                            75          341 ± 33***                                55        365 ± 26***                                                       ______________________________________                                          *P < 0.05                                                                      **P < 0.01                                                                     ***P < 0.001                                                              

What is claimed is:
 1. A benzamide derivative of the formula: ##STR54## wherein R₁ is a hydrogen atom, a methyl group or a methoxy group; R₂ is a hydrogen atom, a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms or a cyclic alkyl group having 5 or 6 carbon atoms or an unsubstituted phenyl group or a phenyl group substituted with a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms on the nucleus; and R₃ is a hydrogen atom or one or two alkyl groups having 1 to 4 carbon atoms.
 2. 3-(3-n-Propylureido)-N-(6-methyl-2-pyridyl)benzamide according to claim
 1. 3. 3-(3-Isopropylureido)-N-(6-methyl-2-pyridyl)benzamide according to claim
 1. 4. 3-(3-n-Butylureido)-N-(6-methyl-2-pyridyl)benzamide according to claim
 1. 5. 3-(3-n-Butylureido)-4-methyl-N-(6-methyl-2-pyridyl)benzamide according to claim
 1. 6. 3-(3-n-Butylureido)-4-methoxy-N-(6-methyl-2-pyridyl)benzamide according to claim
 1. 7. 3-(3-Isopropylureido)-N-(4,6-dimethyl-2-pyridyl)benzamide according to claim
 1. 8. 3-Ureido-N-(6-methyl-2-pyridyl)benzamide according to claim
 1. 